1-40092077-ATT-TGA

Variant names:

• chr1-40092077-ATT-TGA
• NM_000310.4:c.328_330delAATinsTCA
• PPT1 p.Asn110Ser

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PS1_Moderate PM1 PM5 PP3

The NM_000310.4(PPT1):​c.328_330delAATinsTCA​(p.Asn110Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. It is difficult to determine the true allele frequency of this variant because it is of type MNV, and the frequency of such variant types in population databases may be underestimated and unreliable. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely pathogenic in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N110D) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: PPT1 NM_000310.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.83
• Publications: 0 publications found

Genes affected

PPT1 (HGNC:9325): (palmitoyl-protein thioesterase 1) The protein encoded by this gene is a small glycoprotein involved in the catabolism of lipid-modified proteins during lysosomal degradation. The encoded enzyme removes thioester-linked fatty acyl groups such as palmitate from cysteine residues. Defects in this gene are a cause of infantile neuronal ceroid lipofuscinosis 1 (CLN1, or INCL) and neuronal ceroid lipofuscinosis 4 (CLN4). Two transcript variants encoding different isoforms have been found for this gene.[provided by RefSeq, Dec 2008]

PPT1 Gene-Disease associations (from GenCC):

• neuronal ceroid lipofuscinosis

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• neuronal ceroid lipofuscinosis 1

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Myriad Women’s Health, Genomics England PanelApp, Orphanet, ClinGen, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Likely_pathogenic. The variant received 7 ACMG points.

• PS1: Transcript NM_000310.4 (PPT1) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar.
• PM1: In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 5 uncertain in NM_000310.4
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr1-40092077-A-T is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 3015048.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP3: No computational evidence supports a deleterious effect, but strongly conserved according to phyloP

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000310.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PPT1	NM_000310.4	MANE Select	c.328_330delAATinsTCA	p.Asn110Ser	missense	N/A	NP_000301.1	P50897-1
	PPT1	NM_001363695.2		c.328_330delAATinsTCA	p.Asn110Ser	missense	N/A	NP_001350624.1	Q5T0S4
	PPT1	NM_001142604.2		c.125-2567_125-2565delAATinsTCA		intron	N/A	NP_001136076.1	P50897-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PPT1	ENST00000642050.2	MANE Select	c.328_330delAATinsTCA	p.Asn110Ser	missense	N/A	ENSP00000493153.1	P50897-1
	PPT1	ENST00000433473.8	TSL:1	c.325_327delAATinsTCA	p.Asn109Ser	missense	N/A	ENSP00000394863.4	A0A2C9F2P4
	PPT1	ENST00000530704.6	TSL:1	n.328_330delAATinsTCA		non_coding_transcript_exon	Exon 3 of 9	ENSP00000431655.1	E9PK48

Frequencies

GnomAD3 genomes Cov.: 33

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		7.8

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

hg19: chr1-40557749;